(a) Field of the Invention
The invention relates to the treatment of neurological disease.
(b) Description of Art
Apolipoprotein E (apoE) functions as a ligand in the process of receptor mediated internalization of lipid-rich lipoproteins. ApoE is probably also involved in reverse lipid transport. In the central nervous system (CNS), apoE plays a central role in the mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity (Poirier J. et al., 1991, Mol. Brain. Res., 9:191–195; Poirier J. et al., 1991, Mol. Brain. Res., 11:97–106; Poirier J. et al., 1993, Neuroscience, 55:81–90). The importance of apoE in the brain is further underscored by the absence of other key plasma apolipoproteins such as apoA1 and apoB in the brain (Roheim P. S. et al., 1979, Proc. Natl. Acad. Sci., 76:4646–4649).
The apoE gene on chromosome 19 has three common alleles (E2, E3, E4), which encode three major apoE isoforms. The frequency of the apoE4 allele has been shown to be markedly increased in sporadic Alzheimer's Disease (AD) (Poirier J. et al., 1993, Apolipoprotein E phenotype and Alzheimer's Disease, Lancet, 342:697–699; Noguchi S. et al., 1993, Lancet (letter), 342:737) and late onset familial Alzheimer's disease (AD) (Corder E. H. et al., 1993, Science, 261:921–923; Payami H. et al., 1993, Lancet (letter), 342:738). This gene dosage effect was observed in both sporadic and familial cases (i.e., as age of onset increases, E4 allele copy number decreases). Women, who are generally at a greater risk of developing Alzheimer's disease, show increased E4 allele frequency when compared to age matched men.
The cholinergic hypothesis of geriatric memory dysfunction raised some fundamental questions regarding the heterogeneity of responses toward different cholinomimetics in AD (Bartus R. T. et al., 1982, Science, 217:408–417). The absence of clear beneficial effects of choline and lecithin on geriatric patients with and without AD is still perplexing. Furthermore, multiple clinical studies using esterases inhibitors such as physostigmine and tacrine have shown that contrary to young subjects, the optimal acute dose necessary to facilitate performance on memory tasks varied considerably among individual aged subjects (Bartus R. T. et al., 1982, Science, 217:408–417).
Neurological diseases provide a unique series of complications for the clinicians, patients, and care givers; the diseases often progress rapidly and disrupt a vast number of major life functions. The progressive nature of these diseases makes the passage of time a crucial issue in the treatment process. Treatment choices in the neurological disease context are complicated by the fact that it often takes a significant period of treatment to determine whether or not a drug is having a therapeutic effect. Accordingly, treatment with the most effective drug or drugs is often delayed while the disease continues to progress. A method which would allow one to predict which patients will respond to specific therapeutics and dosages would provide physical and psychological benefits. As healthcare becomes increasingly inaccessible, the ability to allocate healthcare resources effectively also becomes increasingly important.